Bio-Distribution and Pharmacokinetics of Topically Administered γ-Cyclodextrin Based Eye Drops in Rabbits
The purpose of this study was to evaluate the ocular pharmacokinetics, bio-distribution and local tolerability of γ-cyclodextrin (γCD) based irbesartan 1.5% eye drops and candesartan 0.15% eye drops after single and multiple topical administration in rabbit eyes. In this randomized, controlled study...
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MDPI AG
2021-05-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/5/480 |
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| author | Martin Kallab Kornelia Schuetzenberger Nikolaus Hommer Bhavapriya Jasmin Schäfer Doreen Schmidl Helga Bergmeister Markus Zeitlinger Aimin Tan Phatsawee Jansook Thorsteinn Loftsson Einar Stefansson Gerhard Garhöfer |
| author_facet | Martin Kallab Kornelia Schuetzenberger Nikolaus Hommer Bhavapriya Jasmin Schäfer Doreen Schmidl Helga Bergmeister Markus Zeitlinger Aimin Tan Phatsawee Jansook Thorsteinn Loftsson Einar Stefansson Gerhard Garhöfer |
| author_sort | Martin Kallab |
| collection | DOAJ |
| description | The purpose of this study was to evaluate the ocular pharmacokinetics, bio-distribution and local tolerability of γ-cyclodextrin (γCD) based irbesartan 1.5% eye drops and candesartan 0.15% eye drops after single and multiple topical administration in rabbit eyes. In this randomized, controlled study, a total number of 59 New Zealand White albino rabbits were consecutively assigned to two study groups. Group 1 (<i>n</i> = 31) received irbesartan 1.5% and group 2 (<i>n</i> = 28) candesartan 0.15% eye drops. In both groups, single dose and multiple administration pharmacokinetic studies were performed. Rabbits were euthanized at five predefined time points after single-dose administration, whereas multiple-dose animals were dosed for 5 days twice-daily and then euthanized 1 h after the last dose administration. Drug concentration was measured by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the retinal tissue, vitreous humor, aqueous humor, corneal tissue and in venous blood samples. Pharmacokinetic parameters including maximal drug concentration (C<sub>max</sub>), time of maximal drug concentration (T<sub>max</sub>), half-life and AUC were calculated. To assess local tolerability, six additional rabbits received 1.5% irbesartan eye drops twice daily in one eye for 28 days. Tolerability was assessed using a modified Draize test and corneal sensibility by Cochet Bonnet esthesiometry. Both γCD based eye drops were rapidly absorbed and distributed in the anterior and posterior ocular tissues. Within 0.5 h after single administration, the C<sub>max</sub> of irbesartan and candesartan in retinal tissue was 251 ± 142 ng/g and 63 ± 39 ng/g, respectively. In the vitreous humor, a C<sub>max</sub> of 14 ± 16 ng/g for irbesartan was reached 0.5 h after instillation while C<sub>max</sub> was below 2 ng/g for candesartan. For multiple dosing, the observed C<sub>mean</sub> in retinal tissue was 338 ± 124 ng/g for irbesartan and 36 ± 10 ng/g for candesartan, whereas mean vitreous humor concentrations were 13 ± 5 ng/g and <2 ng/g, respectively. The highest plasma concentrations of both irbesartan (C<sub>max</sub> 5.64 ± 4.08 ng/mL) and candesartan (C<sub>max</sub> 4.32 ± 1.04 ng/mL) were reached 0.5 h (T<sub>max</sub>) after single administration. Local tolerability was favorable with no remarkable differences between the treated and the control eyes. These results indicate that irbesartan and candesartan in γCD based nanoparticle eye drops can be delivered to the retinal tissue of the rabbit’s eye in pharmacologically relevant concentrations. Moreover, safety and tolerability profiles appear to be favorable in the rabbit animal model. |
| first_indexed | 2024-03-10T11:17:24Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T11:17:24Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-b498415de98d43d3b39eb7466bd08c1a2023-11-21T20:18:53ZengMDPI AGPharmaceuticals1424-82472021-05-0114548010.3390/ph14050480Bio-Distribution and Pharmacokinetics of Topically Administered γ-Cyclodextrin Based Eye Drops in RabbitsMartin Kallab0Kornelia Schuetzenberger1Nikolaus Hommer2Bhavapriya Jasmin Schäfer3Doreen Schmidl4Helga Bergmeister5Markus Zeitlinger6Aimin Tan7Phatsawee Jansook8Thorsteinn Loftsson9Einar Stefansson10Gerhard Garhöfer11Department of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, AustriaCenter for Medical Physics and Biomedical Engineering, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, AustriaCenter for Medical Physics and Biomedical Engineering, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, AustriaCenter for Biomedical Research, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, AustriaNucro-Technics, Toronto, ON M1H 2W4, CanadaPharmaceutics and Industrial Pharmacy, Chulalongkorn University, Bangkok 10330, ThailandFaculty of Pharmaceutical Science, University of Iceland, 107 Reykjavik, IcelandDepartment of Ophthalmology, University of Iceland, 101 Reykjavik, IcelandDepartment of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, AustriaThe purpose of this study was to evaluate the ocular pharmacokinetics, bio-distribution and local tolerability of γ-cyclodextrin (γCD) based irbesartan 1.5% eye drops and candesartan 0.15% eye drops after single and multiple topical administration in rabbit eyes. In this randomized, controlled study, a total number of 59 New Zealand White albino rabbits were consecutively assigned to two study groups. Group 1 (<i>n</i> = 31) received irbesartan 1.5% and group 2 (<i>n</i> = 28) candesartan 0.15% eye drops. In both groups, single dose and multiple administration pharmacokinetic studies were performed. Rabbits were euthanized at five predefined time points after single-dose administration, whereas multiple-dose animals were dosed for 5 days twice-daily and then euthanized 1 h after the last dose administration. Drug concentration was measured by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the retinal tissue, vitreous humor, aqueous humor, corneal tissue and in venous blood samples. Pharmacokinetic parameters including maximal drug concentration (C<sub>max</sub>), time of maximal drug concentration (T<sub>max</sub>), half-life and AUC were calculated. To assess local tolerability, six additional rabbits received 1.5% irbesartan eye drops twice daily in one eye for 28 days. Tolerability was assessed using a modified Draize test and corneal sensibility by Cochet Bonnet esthesiometry. Both γCD based eye drops were rapidly absorbed and distributed in the anterior and posterior ocular tissues. Within 0.5 h after single administration, the C<sub>max</sub> of irbesartan and candesartan in retinal tissue was 251 ± 142 ng/g and 63 ± 39 ng/g, respectively. In the vitreous humor, a C<sub>max</sub> of 14 ± 16 ng/g for irbesartan was reached 0.5 h after instillation while C<sub>max</sub> was below 2 ng/g for candesartan. For multiple dosing, the observed C<sub>mean</sub> in retinal tissue was 338 ± 124 ng/g for irbesartan and 36 ± 10 ng/g for candesartan, whereas mean vitreous humor concentrations were 13 ± 5 ng/g and <2 ng/g, respectively. The highest plasma concentrations of both irbesartan (C<sub>max</sub> 5.64 ± 4.08 ng/mL) and candesartan (C<sub>max</sub> 4.32 ± 1.04 ng/mL) were reached 0.5 h (T<sub>max</sub>) after single administration. Local tolerability was favorable with no remarkable differences between the treated and the control eyes. These results indicate that irbesartan and candesartan in γCD based nanoparticle eye drops can be delivered to the retinal tissue of the rabbit’s eye in pharmacologically relevant concentrations. Moreover, safety and tolerability profiles appear to be favorable in the rabbit animal model.https://www.mdpi.com/1424-8247/14/5/480γ-cyclodextrinirbesartancandesartanmultiple instillationsingle instillationnanoparticles |
| spellingShingle | Martin Kallab Kornelia Schuetzenberger Nikolaus Hommer Bhavapriya Jasmin Schäfer Doreen Schmidl Helga Bergmeister Markus Zeitlinger Aimin Tan Phatsawee Jansook Thorsteinn Loftsson Einar Stefansson Gerhard Garhöfer Bio-Distribution and Pharmacokinetics of Topically Administered γ-Cyclodextrin Based Eye Drops in Rabbits Pharmaceuticals γ-cyclodextrin irbesartan candesartan multiple instillation single instillation nanoparticles |
| title | Bio-Distribution and Pharmacokinetics of Topically Administered γ-Cyclodextrin Based Eye Drops in Rabbits |
| title_full | Bio-Distribution and Pharmacokinetics of Topically Administered γ-Cyclodextrin Based Eye Drops in Rabbits |
| title_fullStr | Bio-Distribution and Pharmacokinetics of Topically Administered γ-Cyclodextrin Based Eye Drops in Rabbits |
| title_full_unstemmed | Bio-Distribution and Pharmacokinetics of Topically Administered γ-Cyclodextrin Based Eye Drops in Rabbits |
| title_short | Bio-Distribution and Pharmacokinetics of Topically Administered γ-Cyclodextrin Based Eye Drops in Rabbits |
| title_sort | bio distribution and pharmacokinetics of topically administered γ cyclodextrin based eye drops in rabbits |
| topic | γ-cyclodextrin irbesartan candesartan multiple instillation single instillation nanoparticles |
| url | https://www.mdpi.com/1424-8247/14/5/480 |
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